Diminished food-related motivation in adult rats treated with methamphetamine during adolescence

Drug use among adolescents continues to be an area of concern because of the possibility of long-lasting physical and mental changes. The aim of this study was to determine whether methamphetamine exposure during adolescence results in long-lasting neurobehavioral alterations in adulthood. Sprague-Dawley rats were injected with methamphetamine (4 mg/kg/ day) during postnatal days 28-37. Once rats reached postnatal days 150, they were placed in standard operant chambers, where they were trained to respond to a lever for sucrose pellets, the experimental reinforcement. Methamphetamine exposure during adolescence did not result in a noteworthy impairment in the development of the correct lever touch response in the autoshaped learning test with 4 seconds delayed reinforcement. These rats were also tested for the motivation to obtain sucrose pellets under a progressive ratio schedule of the reinforcement on postnatal days 170. Decreased lever-pressing response was noted in male rats exposed to methamphetamine during adolescence, but not in female rats. These results indicate that methamphetamine exposure during adolescence results in a decrease in the motivation for a natural reinforcer later in adulthood, particularly in male rats. From our data, we suggest that male brains are less capable of facilitating recovery than female brains after methamphetamine-induced perturbation of brain function during the adolescent period.ope

TSL Family Therapy Followed by Improved Marital Quality and Reduced Oxidative Stress

Objectives: The current study evaluated the effectiveness of a form of family therapy developed in Korea. The “Thank you – Sorry – Love” (TSL) model was applied to a group of elderly retired men to improve the quality of their marriage and to reduce their stress. Methods: Thirty married retired Korean men were assigned to three groups. Group 1 received 14 sessions over 7 weeks of the TSL intervention. Group 2 received 14 sessions of educational classes related to retirement and aging. Group 3 received nothing. Assessments were made of the men’s marital quality (using the Dyadic Adjustment scale) and oxidative stress (a biological marker of health), pretreatment, posttreatment, and 5 weeks after treatment. The husbands’ wives were assessed in terms of marital quality at similar time points. Results: Husbands who received TSL therapy experienced statistically significant decreased oxidative stress (8-isoprostane levels) and increased marital quality. The spouses of the TSL program participants also showed statistically significant improvement in marital quality. The educational comparison group and no-treatment control group clients did not significantly improve on either measure, nor did their spouses experience improved marital quality. Conclusions: TSL family therapy was followed by both psychosocial (husbands and wives’) and physiological (husbands’) improvements. Additional randomized clinical trials of this promising family therapy may be warranted.ope

G-CSF Mobilized Peripheral Blood Human Hematopoietic CD34+ Stem Cells Therapy for Acute Stroke: Preliminary Results

Objective：Acute stroke caused by cerebral artery occlusion or rupture is the most important vascular central nervous system disorder in Korea and remains a leading cause of death and disability despite significant clinical benefits after current treatment modalities. Therefore, it is crucial to develop new alternative therapeutic strategies. The most encouraging approach is directed towards cell transplantation into damaged regions. We discuss the ideal candidate for cell transplantation in current status and preliminary results of peripheral blood stem cells transplantation for acute stroke. Methods : Five patients with acute stroke (three patients with deep intracerebral hemorrhage and two patients with middle cerebral artery occlusion) underwent peripheral blood stem cells transplantation stereotactically. Results : Cell transplantation of three patients did not improve motor function recovery, as evidenced by NIHSS. However, interestingly, cell transplantation significantly increased CSF levels of vascular endothelial growth factor (VEGF). Conclusion : Cell transplantation did correlate positively with elevated growth factor levels in CSF, but not with improved motor function.ope

Zinc Inhibits Amyloid beta Production from Alzheimer's Amyloid Precursor Protein in SH-SY5Y Cells

Zinc released from excited glutamatergic neurons accelerates amyloid beta (Abeta) aggregation, underscoring the therapeutic potential of zinc chelation for the treatment of Alzheimer's disease (AD). Zinc can also alter Abeta concentration by affecting its degradation. In order to elucidate the possible role of zinc influx in secretase-processed Abeta production, SH-SY5Y cells stably expressing amyloid precursor protein (APP) were treated with pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and the resultant changes in APP processing were examined. PDTC decreased Abeta40 and Abeta42 concentrations in culture media bathing APP-expressing SH-SY5Y cells. Measuring the levels of a series of C-terminal APP fragments generated by enzymatic cutting at different APP-cleavage sites showed that both beta- and alpha-cleavage of APP were inhibited by zinc influx. PDTC also interfered with the maturation of APP. PDTC, however, paradoxically increased the intracellular levels of Abeta40. These results indicate that inhibition of secretase-mediated APP cleavage accounts -at least in part- for zinc inhibition of Abeta secretion.ope

The Temporal Changes of Matrix Metalloproteinases in Experimental Middle Cerebral Artery Occlusion and Reperfusion

Background: Matrix metalloproteinases (MMPs) can degrade a wide range of extracellular matrix components. The degradation of microvascular basal lamina by MMPs may be, in part, responsible for the hemorrhagic transformation, brain edema, and accentuation of ischemic injury in cerebral ischemia. Although MMP-2 and MMP-9 were reported to increase in cerebral ischemia, the temporal patterns of their increase are uncertain. Methods: By using gelatin zymogra-phy, we investigated the activity of MMP-2 and MMP-9 in 10 ㎛ frozen sections of ischemic and non-ischemic hemi-spheres in spontaneous hypertensive rats (SHRs) after variable time of reperfusion following 2 hours of middle cerebral artery occlusion (MCA:O). Adjacent 2㎜-thick slices were stained with 2,3,5-triphenyltetrazolium chloride (TTC) solu-tion to define the area of ischemic damage. Results: The infarcted zone could be visualized well by TTC staining after 3 hours of reperfusion. MMP-2 was observed in all samples examined, while MMP-9 was observed only in the ischemic hemispheres. In the ischemic hemispheres when comparing with non-ischemic sides, MMP-9 was increased in all groups undergoing MCA:O, as early as in 2 hours of MCA:O group, while MMP-2 was increased only after 6 days in the reperfu-sion group. MMP-2 and MMP-9 activities per unit volume of infarction increased during the reperfusion period and were highest after 6 days. ConclusIons: MMP-9 increased early after MCA:O in the SHR and both MMP-2 and MMP-9 increased during the reperfusion period. These findings highlight the early potential role of MMP-9 in cerebral ischemia.ope

Developmental Disability Animal Model Based on Neonatal Lipopolysaccharide with Altered 5-HT Function

Developmental disability shows life-long behavioral abnormality with no significant physical malformation. This study was undertaken to develop an animal model for developmental disability by using two-factor approach. Lipopolysaccharide (LPS), a bacterial toxin, and NAN-190, a 5-HT1A receptor antagonist, were administered to Sprague-Dawley rats on postnatal day (PND) 5 to induce inflammation and an altered 5-HT system, respectively. Long-term alteration of behavior occurred in the drug-treated groups. The LPS-treated group showed impaired motor coordination in the Rota-rod test. The LPS- treated or both LPS and NAN-190-treated groups showed impaired fore-paw muscle power in the wire maneuver test. These groups also showed decreased white matter volume and increased serotonergic fibers. The LPS and NAN-190-treated group also exhibited neurologic deficit in the placing reaction test and impaired equilibrium function in the tilt table test. The results showed that a variety of altered behaviors can be generated by two factor model, and suggested that combination of important etiologic factors and possible underlying defects is a promising strategy of establishing an animal model for developmental disabilities.ope

Slitrks control excitatory and inhibitory synapse formation with LAR receptor protein tyrosine phosphatases

The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory–inhibitory balance.ope

Changes in brain metabolic connectivity underlie autistic-like social deficits in a rat model of autism spectrum disorder

The neurobiological basis of social dysfunction and the high male prevalence in autism spectrum disorder (ASD) remain poorly understood. Although network alterations presumably underlie the development of autistic-like behaviors, a clear pattern of connectivity differences specific to ASD has not yet emerged. Because the heterogeneous nature of ASD hinders investigations in human subjects, we explored brain connectivity in an etiologically homogenous rat model of ASD induced by exposure to valproic acid (VPA) in utero. We performed partial correlation analysis of cross-sectional resting-state 18F-fluorodeoxyglucose positron emission tomography scans from VPA-exposed and control rats to estimate metabolic connectivity and conducted canonical correlation analysis of metabolic activity and behavior scores. VPA-treated rats exhibited impairments in social behaviors, and this difference was more pronounced in male than female rats. Similarly, current analyses revealed sex-specific changes in network connectivity and identified distinct alterations in the distributed metabolic activity patterns associated with autistic-like social deficits. Specifically, diminished activity in the salience network and enhanced activity in a cortico-cerebellar circuit correlated with the severity of social behavioral deficits. Such metabolic connectivity features may represent neurobiological substrates of autistic-like behavior, particularly in males, and may serve as a pathognomonic sign in the VPA rat model of ASD.ope

PKC phosphorylation regulates mGluR5 trafficking by enhancing binding of Siah-1A.

Glutamate is the major excitatory neurotransmitter in the mammalian CNS and acts on both ionotropic and metabotropic glutamate receptors (mGluRs). The mGluRs are widely distributed in the CNS and modulate a variety of neuronal processes, including neurotransmitter release and ion channel function. In hippocampus and cortex, mGluR5 is highly expressed and plays an important role in the regulation of synaptic plasticity. Calmodulin (CaM) binding dynamically regulates mGluR5 surface expression; however, the mechanisms linking CaM to mGluR5 trafficking are not clear. Recent studies showed that CaM binding to mGluR7 regulates its trafficking in a phosphorylation-dependent manner by disrupting the binding of protein interacting with C kinase 1. The E3 ligase seven in absentia homolog (Siah)-1A binds to mGluR5 and competes with CaM binding, making it an intriguing molecule to regulate phosphorylation-dependent trafficking of mGluR5. In the present study, we find that CaM competes with Siah-1A for mGluR5 binding in a phosphorylation-dependent manner in rat hippocampal neurons. Specifically, phosphorylation of mGluR5 S901 favors Siah-1A binding by displacing CaM. We identified critical residues regulating Siah-1A binding to mGluR5 and showed that binding is essential for the Siah-1A effects on mGluR5 trafficking. Siah-1A binding decreases mGluR5 surface expression and increases endosomal trafficking and lysosomal degradation of mGluR5. Thus CaM-regulated Siah-1A binding to mGluR5 dynamically regulates mGluR5 trafficking. These findings support a conserved role for CaM in regulating mGluR trafficking by PKC-dependent regulation of receptor-binding proteinsope

Behavioral Testing for Therapeutic Outcome Measurements in an Animal Model of Huntington's Disease

Objective: To investigate which outcome measurements are useful for detecting functional changes after therapeutic approach to delayed motor impairment in an animal model of Huntington's disease (HD). Method: R6/2 transgenic mice received intraventricular injections of adenoviral BDNF/noggin (AdB/N), AdBDNF, AdNull (n=15 each) at 4 weeks of age. Untreated R6/2s and wild-type mice were also recruited as controls. Motor performance was measured using rotarod analysis and locomotor activity test at regular intervals until preterminal age of 13 weeks. Results: On constant speed rotarod testing, AdB/N-treated R6/2s exhibited a delayed disease progression after post operative 6 weeks. AdB/N also ameliorated general locomotor activity deficits. One min-rotarod analysis showed a delayed motor impairment in AdBDNF group at preterminal age compared with AdNull and untreated controls, which was not shown in 3 min and 5 min-rotarod. Accelerating rotarod paradigm was not superior to constant speed. Partial therapeutic effects on locomotor activities were detected in total 60 min-monitoring, but not in 30 min- or 10 minmonitoring. Conclusion: Appropriate behavioral testing and outcome measurements should be selected to detect the treatment effect to slow functional deterioration in HD.ope